Many pathogenic mechanisms contribute to the eventual decline of the immune system during HIV infection, including viral mutation and escape from the immune response, loss of CD4 cell-derived help, loss of antigen presenting cell function, cytokine perturbation, and loss of thynuc and bone marrow hematopoietic function. All of these factors likely help pave the way for greater virus replication and decreased ability to respond to antigenic insult. Recently our laboratory and others have identified another mechanism that may contribute to loss of CD8 cell function during HIV infection. Following costimulation in vitro, CD8+ lymphocytes express the CD4 molecule, which renders them susceptible to HIV infection. This could result in death of the infected CD8 cell or contribute to the reservoir of infected cells in vivo. We propose herein to further study the expression of CD4 on CD8+ lymphocytes. We will explore factors contributing to expression of this molecule during CD8 cell activation, as well as its importance in the immune response in vivo by addressing the following Specific Aims: 1) To further explore the acquisition of CD4 on CD8 cells following stimulation; 2) To determine the function(s) of CD4 on CD8 cells; 3) To determine whether antigenic activation induces expression of CD4 on CD8 cells in vivo; 4.) To determine if CD4 expression by CD8 cells is required for optimal CD8 cell responses against viral infection. The experiments outlined in this proposal will help us understand the role of CD4 on CD8 T cells, and allow us to determine the function of the previously overlooked CD8+/CD4dim subset seen in vivo. In addition, our studies will help us understand what effects HIV infection of this subset might have on the antiviral immune response, and allow us to postulate the effects of loss of these cells on HIV disease progression.